Total submissions: 10
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000169485 | SCV000852135 | pathogenic | Phenylketonuria | 2018-08-10 | reviewed by expert panel | curation | PAH-specific ACMG/AMP criteria applied: PM2: MAF = 2.0e-5; PP3: Software agrees on a damaging effect.; PS3: Mutation ID#1, 18% residual enzyme activity (PMID:18590700); PM3: I306V / F55L (pathogenic in ClinVar) in a single patient with mild HPA (PMID:18299955); PP4_Moderate: BH4 defect excluded in all patients--single patient with mild hyperphe (Bercovich, 2008). (PMID:18299955). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PS3, PM3, PP4_Moderate). |
Fulgent Genetics, |
RCV000169485 | SCV000611226 | likely pathogenic | Phenylketonuria | 2017-05-18 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000169485 | SCV000696473 | pathogenic | Phenylketonuria | 2017-05-22 | criteria provided, single submitter | clinical testing | Variant summary: The PAH c.916A>G (p.Ile306Val) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 1/121200 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). The variant was reported in numerous individuals in the literature, mainly associated with mild-PKU or hyperphenylalaninemia. In addition, in vitro assays show the variant to result in reduced PAH activity. Multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic. |
Labcorp Genetics |
RCV000169485 | SCV000833414 | pathogenic | Phenylketonuria | 2024-01-18 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 306 of the PAH protein (p.Ile306Val). This variant is present in population databases (rs62642934, gnomAD 0.003%). This missense change has been observed in individuals with PAH-related disease (PMID: 1358789, 18299955, 23430547, 23764561). ClinVar contains an entry for this variant (Variation ID: 618). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PAH protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 11161839, 17924342, 25596310). For these reasons, this variant has been classified as Pathogenic. |
Ce |
RCV000089157 | SCV001249174 | pathogenic | not provided | 2019-06-01 | criteria provided, single submitter | clinical testing | |
Baylor Genetics | RCV000169485 | SCV004209608 | pathogenic | Phenylketonuria | 2023-12-26 | criteria provided, single submitter | clinical testing | |
OMIM | RCV000000649 | SCV000020799 | pathogenic | Hyperphenylalaninemia | 1992-09-01 | no assertion criteria provided | literature only | |
De |
RCV000089157 | SCV000119771 | not provided | not provided | no assertion provided | not provided | ||
Counsyl | RCV000169485 | SCV000220937 | pathogenic | Phenylketonuria | 2016-01-21 | no assertion criteria provided | clinical testing | |
Natera, |
RCV000169485 | SCV001463131 | pathogenic | Phenylketonuria | 2020-09-16 | no assertion criteria provided | clinical testing |